The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells

Abstract

Systemic gamma-aminobutyric acid (GABA) therapy prevents or ameliorates type 1 diabetes (T1D), by suppressing autoimmune responses and stimulating pancreatic beta cells. In beta cells, it increases insulin secretion, prevents apoptosis, and induces regeneration. It is unclear how GABA mediates these effects. We hypothesized that Klotho is involved. It is a multi-functional protein expressed in the kidneys, brain, pancreatic beta cells, other tissues, and is cell-bound or soluble. Klotho knockout mice display accelerated aging, and in humans Klotho circulating levels decline with age, renal disease and diabetes. Here, we report that GABA markedly increased circulating levels of Klotho in streptozotocin (STZ)-induced diabetes. GABA also increased Klotho in the islet of Langerhans of normal mice, as well as the islets and kidneys of STZ-treated mice. In vitro, GABA stimulated production and secretion of Klotho by human islet cells. Knockdown (KD) of Klotho with siRNA in INS-1E insulinoma cells abrogated the protective effects of GABA against STZ toxicity. Following KD, soluble Klotho reversed the effects of Klotho deficiency. In human islet cells soluble Klotho protected against cell death, and stimulated proliferation and insulin secretion. NF-κB activation triggers beta-cell apoptosis, and both GABA and Klotho suppress this pathway. We found Klotho KD augmented NF-κB p65 expression, and abrogated the ability of GABA to block NF-κB activation. This is the first report that GABAergic stimulation increases Klotho expression. Klotho protected and stimulated beta cells and lack of Klotho (KD) was reversed by soluble Klotho. These findings have important implications for the treatment of T1D.

Combined effect of GABA and glucagon‐like peptide‐1 receptor agonist on cytokine‐induced apoptosis in pancreatic β‐cell line and isolated human islets

“…The expression of α‐Klotho (henceforth “Klotho”) is also enhanced by GABA in human β‐cells . Klotho has previously been reported to have antiapoptotic effects on β‐cells .…”

“…We recently reported that GABA treatment markedly increases Klotho production by human β‐cells . Notably, like SIRT1, Klotho protected against apoptosis and suppressed NF‐κB activation …”

“…In addition to SIRT1, several other proteins are likely to be involved in the antiapoptotic effect of GABA, such as Klotho . Klotho has several effects in mice that resemble GABA therapy, such as improved β‐cell survival and insulin secretion .…”

“…In humans, circulating concentrations of Klotho are decreased in individuals with either T1D or type 2 diabetes . We recently reported that GABA treatment markedly increases Klotho production by human β‐cells . Notably, like SIRT1, Klotho protected against apoptosis and suppressed NF‐κB activation …”

Gimmicks of gamma‐aminobutyric acid (GABA) in pancreatic β‐cell regeneration through transdifferentiation of pancreatic α‐ to β‐cells

“…However, NF-κB activation triggered β-cell apoptosis, while both GABA and Klotho are suppressors of this pathway. Hence, Klotho protects β cells through GABAergic stimulation, and the increased Klotho expression suppresses NF-κB signaling activation (Prud'homme et al, 2017). Regarding the preferment of β-cell death due to the activation of NF-κB, its blockade through GABA may be an essential aspect in preventing T1D.…”